Nor-tropane derivatives

ABSTRACT

There are disclosed nor-tropane derivatives substituted at the 3 position with aroylamino or heteroaroylamino and substituted at the 8 position with benzyl, substituted benzyl, 2-methyl thiophene, 3-methyl thiophene, 2-methyl furan or cyclohexylmethyl. The compounds are prepared by condensing the carboxylic acids corresponding to said aroyl or heteroaroyl group with the corresponding β-3-amino-8-substituted nor-tropanes. The compounds possess neuroleptic properties.

The present invention relates to novel nor-tropane derivatives andparticularly novel 3-aroylamino and 3-heteroaroylamino nor-tropanes,substituted in position 8, a process for preparing same and theirapplication in therapeutics.

These new derivatives comply more precisely with the formula: ##STR1##in which R represents:

either a benzyl nucleus, in which case A--CO-- designates:

a 5-pyrimidinyl carbonyl nucleus of formula: ##STR2##

an aroyl nucleus of formula: ##STR3## in which the pair (R₁, R₂) assumesany one of the following values: (CH₃, H), (CH₃, F), (CH₃, NO₂), (CH₃,OH);

an aroyl nucleus of formula: ##STR4## in which the set (R₃, R₄, R₅)assumes any one of the following values: (CH₃, NH₂, Br), (CH₃, CH₃ CONH,Br), (CH₃, CF₃ CONH, Br), (CH₃, CH₃ CONH, Cl), (CH₃, CF₃ CONH, Cl), (C₂H₅, NH₂, Br), (CH₃, NH₂, H), (CH₃, CH₃ O, CH₃ O), (CH₃, CH₃ O, H);

an aroyl nucleus polysubstituted by the following groups or atoms:dimethoxy-2,3; dimethoxy-3,5; trimethoxy-2,3,4; methoxy-2 dibromo-3,5amino-4;

or a benzyl nucleus monosubstituted in the meta position of formula:##STR5## in which R₆ represents a methyl or trifluoromethyl group or ahalogen atom, in which case A--CO-- designates the 2-methoxy-4-amino5-bromo benzoyl nucleus of formula: ##STR6##

or a benzyl nucleus monosubstituted in the para position of formula:##STR7## in which R₇ represents:

a methyl or methoxy group or an atom of bromine or chlorine, in whichcase A--CO-- represents the 2-amino 4-methoxy 5-pyrimidinyl carbonylnucleus of formula: ##STR8##

a lower alkyl or a trifluoromethyl group or an atom of chlorine, bromineor fluorine, in which case A--CO-- represents a 2-methoxy 4-amino5-bromo benzoyl nucleus,

or a 3,4-dichloro benzyl group, a 2-methyl thiophene group ##STR9## or a3-methyl thiophene group ##STR10## in which case A--CO-- represents a2-methoxy 4-amino 5-bromo benzoyl nucleus;

or a 2-methyl thiophene, a 3-methyl thiophene or a 2-methyl furane group##STR11## in which case A--CO-- represents a 2-methoxy 4-amino 5-chlorobenzoyl nucleus;

or a cyclohexylmethyl group, in which case A--CO-- represents a2-methoxy 4-amino 5-bromo benzoyl nucleus.

It should be noted that in formula (I), the chain A--CO--NH is in theequatorial position and the nor-tropanes having such a substituent inthe equatorial position will be called β in what follows.

The present invention comprises of course as well the pharmaceuticallyacceptable mineral or organic acids addition salts of said compounds.

The compounds of formula (I) are obtained by condensing, by the mixedanhydrides method, the acids of formula:

    A--COOH                                                    (II)

in which A--CO-- has the same meanings as A--CO-- in formula (I), withthe corresponding β-3-amino nor-tropanes of formula: ##STR12## in whichR has the same meaning as in formula (I).

The compounds of formula (II) complying more precisely with theparticular formula: ##STR13## in which R₈ represents a methoxy or anethoxy group, are new and are obtained by saponification of the compoundof formula: ##STR14## in which R₈ has the same meanings as in formula(IIa) and R₉ represents a methyl or ethyl group.

The compounds of formula (IV) in which the couple (R₈, R₉) assumes thefollowing values: (OCH₃, CH₃) and (OC₂ H₅, C₂ H₅) are also new and areobtained by a 3-stage synthesis which consists in treating 2-amino5-ethoxycarbonyl 4-hydroxy pyrimidine, in solution in a basic organicsolvent, such as pyridine, with an acid anhydride (e.g. aceticanhydride), then in reacting the product thus obtained with achlorinating agent preferably phosphorous oxychloride, and finally incausing to react on the resulting new product, sodium methylate orethylate, respectively in solution in methanol or ethanol.

The compound of formula (III) in which R represents the benzyl group isnew and results from the reduction, by means of sodium in amyl alcohol,of the oxime of N-benzyl nor-tropine-3 one of formula: ##STR15##

The compounds of formula (III) in which R has the same meanings as informula (I), with the exception of the benzyl group, are also new andare obtained by a two-stage synthesis which consists in condensingcyclohexylmethyl chloride, 3,4-dichloro benzyl chloride, 2-chloromethylthiophene, 3-chloromethyl thiophene, 2-chloromethyl furane or thechlorides of formulae: ##STR16## in which R₆ and R₇ have the samemeanings as in formula (I), on the compounds of formula: ##STR17## inwhich R₁₀ represents the methyl or ethoxy group, this condensation beingpreferably carried out at reflux in an organic solvent such as acetone,acetonitrile or DMF in the presence of potassium carbonate ortriethylamine, then in hydrolyzing the acetyl or carbethoxy group.

The compounds of formula (VII), which are new, are obtained by atwo-stage synthesis consisting in treating the compound of formula (III)in which R represents the benzyl group, with acetyl chloride or ethylchloroformiate, in a tetrahydrofurane medium and in the presence of anorganic base such as pyridine or triethylamine, then in hydrogenolyzingthe product obtained, for example in the presence of palladium oncharcoal at 10% in an ethanol medium, at a temperature of 60° C. and ata pressure of 15 bars.

The compounds of formula (I) where the motif A--CO-- represents thegroup of formula: ##STR18## and wherein R is different from the benzylgroup, may also be obtained by condensation of the compounds of formula(VIa) with the compound of formula: ##STR19##

This condensation is preferably carried out in accordance with a processidentical to the one used for the synthesis of the compounds of formula(III) where R is different from the benzyl group.

Finally, the compound of formula (VIII), also new, is obtained byhydrogenolysis--preferably in an acid medium, in the presence ofpalladium on charcoal at 10%, at room temperature, at a pressure of 90mbars and in an alcohol medium--of the compound of formula: ##STR20##

This latter compound is prepared in accordance with the processdescribed above for the preparation of the compounds of formula (I)[mixed anhydrides method] by condensing acid of formula: ##STR21## withthe compound of formula (III) wherein R is a benzyl group.

The acid addition salts of the compounds of formula (I) may be obtainedby usual methods. For example the acid, e.g. hydrochloric, oxalic,maleic or fumaric acid, is added to the compounds of formula (I) in baseform, in the presence of an appropriate solvent such as ethanol forexample.

The following preparations are given by way of examples to illustratethe invention.

EXAMPLE 1 β-3-[(4-amino 5-bromo 2-methoxy) benzoyl] aminoN-parafluorobenzyl nor-tropane, chlorhydrate (I)

Code number: 19

To a solution of 8.35 g of 4-amino 5-bromo 2-methoxy benzoic acid (II)in 200 ml of tetrahydrofurane cooled to 0° C., were added 5.18 ml oftriethylamine, then 3.5 ml of ethyl chloroformiate. After 45 minutes at0° C., 8.6 g of β-3-amino N-parafluorobenzyl nor-tropane [(III),prepared as in example 5, code No. 103] were added and left to agitatefor 3 hours. The solvent was evaporated, the residue taken up inmethylene chloride, washed with carbonated water, then with water, driedon sodium sulfate, filtered and the solvent evaporated. The residue wascrystallized in isopropylic ether. It was filtered and the precipitateobtained (12.9 g) was dissolved in 150 ml of ethanol; chlorhydricethanol ≃6.5N was added, the precipitate obtained was filtered, rincedwith ether on the filter and recrystallized in absolute alcohol. 5 g ofthe expected product were obtained.

Yield: 36%

Melting point: >265° C.

Molecular weight: 498.82

Empirical formula: C₂₂ H₂₆ BrClFN₃ O₂

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             52.97       5.25   8.42                                          Obtained (%) 52.91       4.93   8.26                                          ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundsof formula (I) appearing in table I below were obtained.

    TABLE I      ##STR22##          Melting   Code  Molecular point Yield ELEMENTARY ANALYSIS No. ACO R F     orm Empirical formula weight (°C.) (%) % C H N      3     ##STR23##      ##STR24##      maleate C.sub.25 H.sub.31 N.sub.5 O.sub.6 497.54 217 62 Cal.Obt.     60.3560.08 6.286.25 14.0814.13      8     ##STR25##      ##STR26##      Base C.sub.20 H.sub.24 ClN.sub.5 O.sub.2 401.89 185 62 Cal.Obt.     59.9759.69 6.026.00 17.4317.35      9 "     ##STR27##      " C.sub.21 H.sub.27 N.sub.5 O.sub.3 397.47 180 65 Cal.Obt. 63.4563.66     6.857.10 17.6217.66      10 "     ##STR28##      " C.sub.21 H.sub.27 N.sub.5 O.sub.2 381.47 178 71 Cal.Obt. 66.1266.20     7.137.15 18.3678.31      16     ##STR29##      ##STR30##      " C.sub.22 H.sub.26 BrN.sub.3 O.sub.2 444.36 209 65 Cal.Obt. 59.4659.37 5     .906.00 9.469.66      19     ##STR31##      ##STR32##      HCl C.sub.22 H.sub.26 BrClFN.sub.3 O.sub.2 498.82 >260  36 Cal.Obt.     52.9752.91 5.254.93 8.428.26      20 "     ##STR33##      Base C.sub.22 H.sub.25 Br.sub.2 N.sub.3 O.sub.2 523.26 223 67 Cal.Obt.     50.4950.68 4.824.67 8.037.86      21 "     ##STR34##      " C.sub.23 H.sub.25 BrF.sub.3 N.sub.3 O.sub.2 529.36 165 72 Cal.Obt.     53.9153.85 4.924.68 8.208.05      22 "     ##STR35##      " C.sub.22 H.sub.25 BrClN.sub.3      O.sub.2 478.81 216 70 Cal.Obt. 55.1855.12 5.265.24 8.788.86  23 "      ##STR36##      " C.sub.23 H.sub.28 BrN.sub.3 O.sub.2 458.39 217 71 Cal.Obt. 60.2660.44 6     .166.13 9.179.27      24 "     ##STR37##      " C.sub.23 H.sub.28 BrN.sub.3 O.sub.2 " 192 64 Cal.Obt. 60.2660.28     6.166.41 9.179.23      25 "     ##STR38##      " C.sub.22 H.sub.25 BrClN.sub.3      O.sub.2 478.81 189 58 Cal.Obt. 55.1855.48 5.265.11 8.768.77  26 "      ##STR39##      " C.sub.22 H.sub.25 BrFN.sub.3      O.sub.2 462.35 167 55 Cal.Obt. 57.1557.43 5.455.29 9.099.01  27 "      ##STR40##      " C.sub.22 H.sub.25 Br.sub.2 N.sub.3 O.sub.2 523.26 204 78 Cal.Obt.     50.4950.58 4.824.79 8.038.27      28 "     ##STR41##      " C.sub.22 H.sub.24 BrCl.sub.2 N.sub.3 O.sub.2 513.26 193 76 Cal.Obt.     51.4851.67 4.714.77 8.198.40      29 "     ##STR42##      " C.sub.20 H.sub.24 BrN.sub.3 O.sub.2      S 450.39 213 54 Cal.Obt. 53.3353.15 5.375.26 9.339.40      30 "     ##STR43##      " C.sub.24 H.sub.30 BrN.sub.3 O.sub.2 472.41 182 81 Cal.Obt. 61.0160.92 6     .406.45 8.908.98      32 "     ##STR44##      " C.sub.20 H.sub.24 BrN.sub.3 O.sub.2      S 450.39 220 67 Cal.Obt. 53.3353.40 5.37 5.44 9.339.31      33 "     ##STR45##      " C.sub.23 H.sub.25 BrF.sub.3 N.sub.3 O.sub.2 512.36 201 58 Cal.Obt.     53.9253.74 4.924.93 8.208.33      35 "     ##STR46##      Maleate+4/5 H.sub.2 O C.sub.26 H.sub.36 BrN.sub.3 O.sub.6+ 4/5 H.sub.2     O 566.48 160 48 Cal.Obt. 53.7653.50 6.526.16 7.237.33      37     ##STR47##      ##STR48##      HCl C.sub.20 H.sub.25 BrClN.sub.5 O.sub.2 482.81 230 51 Cal.Obt.     49.7549.56 5.225.15 14.5114.58      40     ##STR49##      ##STR50##      HCl+1/6 H.sub.2 O C.sub.24 H.sub.29 BrClN.sub.3 O.sub.3+ 1/6 H.sub.2 O     543.88 217 54 Cal.Obt. 52.9953.25 5.815.61 7.737.76      41     ##STR51##      " Base C.sub.24 H.sub.25 BrF.sub.3 N.sub.3 O.sub.3 540.37 191 90     Cal.Obt. 53.3453.64 4.664.92 7.787.92      42     ##STR52##      " " C.sub.24 H.sub.28 ClN.sub.3      O.sub.3 441.94 180 63 Cal.Obt. 65.2264.99 6.396.69 9.519.34  43      ##STR53##      " " C.sub.24 H.sub.25 ClF.sub.3 N.sub.3 O.sub. 3 495.92 181 63 Cal.Obt. 5     8.1258.35 5.085.35 8.478.60      48     ##STR54##      " " C.sub.22 H.sub.25 N.sub.3 O.sub.4 395.44 138 77 Cal.Obt. 66.8266.59 6     .376.55 10,6310.79      49     ##STR55##      " " C.sub.22 H.sub.25 N.sub.2 FO.sub.2 368.44      96 81 Cal.Obt. 71.7171.60 6.847.10 7.607.65      51     ##STR56##      " " C.sub.22 H.sub.26 N.sub.2 O.sub.3 366.44 195 57 Cal.Obt. 72.1072.29 7     .157.42 7.657.62      60     ##STR57##      " " C.sub.24 H.sub.30 N.sub.2 O.sub.4 410.49 130 73 Cal.Obt. 70.2270.07 7     .377.18 6.826.72      61     ##STR58##      " HCl+3/5 H.sub.2 O C.sub.24 H.sub.31 ClN.sub.4 O.sub.2+ 3/5 H.sub.2 O     457.77 220 57 Cal.Obt. 62.9763.26 7.097.11 6.126.08      62     ##STR59##      " HCl+1/5 H.sub.2 O C.sub.22 H.sub.27 ClN.sub.2 O.sub.2+ 1/5 H.sub.2 O     390.51 >260  61 Cal.Obt. 68.2967.78 7.037.36 7.247.46      64     ##STR60##      " Base+2/3 H.sub.2 O C.sub.23 H.sub.28 N.sub.2 O.sub.3+ 2/3 H.sub.2 O     392.48 78 85 Cal.Obt. 70.3870.23 7.507.39 7.147.04 67      ##STR61##      " Base C.sub.22 H.sub.27 N.sub.3 O.sub.2 365.46 145 47 Cal.Obt.     72.3072.40 7.457.78 11.5011.37      68     ##STR62##      " HCl C.sub.23 H.sub.29 ClN.sub.2 O.sub.3 416.93 209 53 Cal.Obt.     66.2566.18 7.017.11 6.726.85      71     ##STR63##      ##STR64##      Base C.sub.20 H.sub.24 ClN.sub.3 O.sub.3 389.87 220 51 Cal.Obt.     61.6161.92 6.216.34 10.7811.02      72 "     ##STR65##      " C.sub.20 H.sub.24 ClN.sub.3      O.sub.2 S 405.94 227 58 Cal.Obt. 59.1759.15 5.965.91 10.3510.12  73 "      ##STR66##      " C.sub.20 H.sub.24 ClN.sub.3 O.sub.2      S 405.94 215 47 Cal.Obt. 59.1759.13 5.965.64 10.3510.37      74     ##STR67##      ##STR68##      HCl+1,2 H.sub.2 O C.sub.22 H.sub.26 Br.sub.2 ClN.sub.3 O.sub.2+ 1,2     H.sub.2 O 581.35 208 36 Cal.Obt. 45.4545.69 4.924.77 7.237.11  75      ##STR69##      " fumarate C.sub.27 H.sub.32 BrN.sub.3 O.sub.6 574.46 212 45 Cal.Obt.     56.4556.45 5.625.74 7.327.33      83     ##STR70##      ##STR71##      Base C.sub.23 H.sub.28 N.sub.2      O.sub.3 380.47 182 91 Cal.Obt. 72.6072.52 7.427.41 7.367.25

EXAMPLE 2 β-3-[5-(2-amino 4-methoxy pyrimidinyl) carbonyl] aminoN-parachlorobenzyl nor-tropane (I)

Code number: 8

1st stage β-3-[5-(2-amino 4-methoxy pyrimidinyl) carbonyl] aminonor-tropane (VIII)

A solution of 148.5 g of maleate of β-3-[5-(2-amino 4-methoxy4-pyrimidinyl) carbonyl] amino N-benzyl nor-tropane [(I), obtained as inexample 1, melting point 185° C., Empirical formula C₂₀ H₂₅ N₅ O₂ +1/6H₂ O, elementary analysis: Cal. (%)--C: 64.84--H: 6.89--N: 18.91: Obt.(%)--C: 64.62--H: 6.86--N: 19.35], in 1,500 ml of alcohol at 50% washydrogenolyzed in an autoclave at room temperature and at a pressure of90 mbars, in the presence of 25 g of palladium on charcoal at 10%. Itwas filtered, the solvent evaporated, the residue crystallized inacetone and recrystallized in alcohol at 90%. 120 g of the desiredproduct were thus isolated.

Yield: 98%

Melting point: 220° C.

Molecular weight: 412.41

Empirical formula: C₁₇ H₂₅ N₅ O₆ +7/5 H₂ O

Elementary analysis:

    ______________________________________                                        4          C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             48.69       6.01   16.98                                         Obtained (%) 48.97       6.19   16.84                                         ______________________________________                                    

2nd stage β-3-[5-(2-amino 4-methoxy pyrimidinyl) carbonyl] aminoN-parachlorobenzyl nor-tropane (I)

Code number: 8

To a solution of 7 g of succinate of the compound of formula (VIII)previously obtained in 100 ml of acetone were added 9.8 g of potassiumcarbonate, then 4.28 g of para-chlorobenzyl chloride. Then the mixturewas heated to reflux for 39 hours, the solvent was evaporated, theresidue was diluted in water and extracted with chloroform. It was driedon sodium sulfate, the solvent was evaporated, the residue wascrystallized in isopropylic ether and recrystallized in normal butylicalcohol. 5 g of the expected product were thus obtained.

Yield: 70%

Melting point: 185° C.

Molecular weight: 401.89

Empirical formula: C₂₀ H₂₄ ClN₅ O₂

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             59.77       6.02   17.43                                         Obtained (%) 59.69       6.00   17.35                                         ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundsof formula (I) appearing in table I and having code numbers 9, 10, 12and 37 were obtained.

EXAMPLE 3 5-(2-amino 4-methoxy pyrimidinyl) carboxylic acid (IIa)

Code number: 88

1st stage 2-amino 4-methoxy 5-methoxycarbonyl pyrimidine (IV)

Code number: 96

50 g of 2-amino 4-hydroxy 5-ethoxycarbonyl pyrimidine were heated toreflux with 40 ml of acetic anhydride in 300 ml of anhydrous pyridinefor 2 hours. The reaction medium was then frozen, the precipitatefiltered, rinced with acetone and dried. 140 g of the raw product thusobtained (yield 62%) was heated to 60° C. in 900 ml of phosphorousoxychloride for 2 hours. After cooling, 200 ml of ethyl ether were addedwhile stirring; the precipitate formed was then filtered, rinced withether, then thrown on 1 kg of ice and neutralised with a solution ofsodium bicarbonate while stirring. The precipitate was filtered, rincedwith water and dried. 112 g of this intermediate (yield 81%) werestirred for 2 hours in a solution of sodium methanolate at 0° C.,prepared with 46 g of sodium in 800 ml of anhydrous methanol. Once againat the normal temperature, the precipitate was filtered, rinced withwater and dried. 80 g of 2-amino 4-methoxy 5-methoxycarbonyl pyrimidinewere obtained.

Yield: 95%

Melting point: 221° C. (Bu OH)

Chlorhydrate

Empirical formula: C₇ H₁₀ ClN₃ O₃

Molecular weight: 219.631

Melting point: 260° C.

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             38.28       4.59   19.13                                         Obtained (%) 38.28       4.42   19.39                                         ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundof formula (IV) bearing the code number 97: 2-amino 4-ethoxy5-ethoxycarbonyl pyrimidine was prepared.

Empirical formula: C₉ H₁₃ N₃ O₃

Molecular weight: 211.218

Melting point: 190° C. (Bu OH)

    ______________________________________                                        NMR (DMSO):                                                                              δppm                                                                    2 triplets centred at 1.3 ppm 6 H                                             (OCH.sub.2 --CH.sub.3)                                                        2 quadruplets centred at 4.3 ppm 4 H                                          (O--CH.sub.2 --)                                                              1 group centred at 7.2 ppm 2 H                                                (NH.sub.2)                                                                    1 singleton centred at 8.5 ppm 1 H                                            (heteroatomic)                                                     ______________________________________                                    

IR (KBr): γcm⁻¹ 3370 cm⁻¹ (NH₂), 1680 cm⁻¹ ester (COO--C₂ H₅).

2nd stage 5-(2-amino 4-methoxy pyrimidinyl)carboxylic acid (IIa)

Code number: 88

600 g of 2-amino 4-methoxy 5-methoxycarbonyl pyrimidine prepared in thepreceding stage were heated to 65° C. with agitation for 1 hour in amixture of 1.5 l of methanol and 1.5 l of NaOH at 5%. Once cooled, thereaction medium was poured on 4 l of iced water then acidified to pH=3under stirring with concentrated hydrochloric acid. The 5-(2-amino4-methoxy pyrimidinyl) carboxylic acid precipitated, drained, washedwith acetone then dried was obtained with a yield of 88.5%.

Hydrated sodium salt

Empirical formula: C₆ H₆ N₃ O₃ Na, 1.25 H₂ O

Molecular weight: 213. 810

Melting point: 260° C.

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             33.73       4.01   19.67                                         Obtained (%) 34.05       3.73   19.84                                         ______________________________________                                    

By the same process, but from the corresponding reagents, the compoundof formula (IIa) appearing in table II and bearing code number 89, isobtained.

                                      TABLE II                                    __________________________________________________________________________     ##STR72##                                                                                               Melt-                                                                     Molec-                                                                            ing                                                Code           Empirical                                                                             ular                                                                              point                                                                             Yield                                                                             Elementary analysis - NMR spectrum-        No.                                                                              Formula                                                                            R.sub.8                                                                           R.sub.9                                                                          formula weight                                                                            (°C.)                                                                      (%) IR spectrum - Thin layer                   __________________________________________________________________________                                       chromatography                             88 IIa  OCH.sub.3                                                                         -- C.sub.6 H.sub.6 N.sub.3 O.sub.3 Na                                                    213.81                                                                            260 88.5                                                                              %    C    H    N                                          + 1.25 H.sub.2 O    Cal. 33.73                                                                              4.01 19.67                                      (sodium salt)       Obt. 34.05                                                                              3.73 19.84                       89 "    OC.sub.2 H.sub.5                                                                   --                                                                              C.sub.7 H.sub.9 N.sub.3 O.sub.3                                                       183.17                                                                            280 76  NMR spectrum (CF.sub.3 COOH)                                                  δppm                                                                    = 4.75; q; and 1.50; t:                                                       OCH.sub.2CH.sub.3                                                             7.5; m; NH.sub.2                                                              8.8; s; (H at 6)                           96 IV   OCH.sub.3                                                                         CH.sub.3                                                                         C.sub.7 H.sub.10 ClN.sub.3 O.sub.3                                                    219.63                                                                            260 95  %    C    H    N                                          (chlorhydrate)      Cal. 38.28                                                                              4.59 19.13                                                          Obt. 38.28                                                                              4.42 19.39                       97 "    OC.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                  C.sub.9 H.sub.13 N.sub.3 O.sub.3                                                      211.22                                                                            190 92  NMR (DMSO) δppm                                                         = 1.3; 2t; 6H: 2CH.sub.3                                                      = 4.3; 2q; 4H: 2CH.sub.2                                                      = 7.2; m; 2H: NH.sub.2                                                        = 8.5; s; 1H at 6                                                             IR (KBr) bands N.sub.2 at 3370                                                cm.sup.-1                                                                     and COOC.sub.2 H.sub.5 at 1680                                                cm.sup.-1                                  __________________________________________________________________________

EXAMPLE 4 β-3-amino N-benzyl nor-tropane, dimaleate (III)

Code number: 98

A suspension of 60 g of N-benzyl nor-tropane oxime (V) in 750 ml of amylalcohol was heated to 40° C. and 50 g of sodium were introduced at arate such that the temperature of the reaction mixture rose to 135°-140°C. Then the reaction medium was diluted with 300 ml of water, theorganic phase was decanted, and extracted by means of 400 ml of HCl 6N,and the aqueous phase was washed with isopropylic ether. Then, theaqueous phase was alkalized with concentrated potash, extracted withmethylene chloride, dried on sodium sulfate, the solvent was evaporatedand the residue distilled. 83 g yield 59%) of liquid, Eb₀.5 =109°-111°C. was obtained which was added to an acetone solution of maleic acid.The precipitate obtained was filtered and recrystallized in absolutealcohol.

Melting point: 150° C.

Empirical formula: C₂₂ H₂₈ N₂ O₈ +4.5 H₂ O

Molecular weight: 462.87

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             57.08       6.45   6.05                                          Obtained (%) 57.14       6.19   5.92                                          ______________________________________                                    

NMR spectrum of the base (CDCl₃) δppm=7.28, m, and 3.53, s, 7H(benzylic) centred on 3.17, m,: 2H (tropanic) at position 1 and 5centred on 2.82, m,: 1H (tropanic) at position 3 1.52, s, 2 NH₂ protonsbetween 2.20 and 1.15, m, 8 tropanic protons.

(the displacement of the tropanic protons in the presence of Europiumsalt EU(FOD)₃ and particularly of the proton at position 3, as well asthe study of the value of the sum of the couplings of the multipletsignal of the proton at 3, in accordance with the law of KARPLUS, showedthat proton -3 is at an axial position, this by analogy with the NMRspectra in the presence of Europium of the derivatives α and β-3-aminotropane).

EXAMPLE 5 β-3-amino N-parafluorobenzyl nor-tropane (III)

Code number: 103

1st stage β-3-acetamido nor-tropane (VII)

To a solution cooled to 0° C. of 96 g of β-3-amino N-benzyl nor-tropane[(III), code number 98, prepared in example 4] in 70 ml of triethylamineand 900 ml of tetrahydrofurane, were slowly added 28 ml of acetylchloride. After 12 hours at room temperature 50 ml of water were added,the solvent was evaporated, the remaining aqueous phase was extractedwith 200 ml of methylene chloride, washed with water, dried on sodiumsulfate and the solvent was evaporated. 80 g of raw product wereobtained which were dissolved in 1000 ml of alcohol. 1 ml ofhydrochloric alcohol 5N was added and the solution was hydrogenolyzed inthe presence of 8 g of palladium on charcoal at 10% in an autoclave, ata temperature of 60° C. and a pressure of 15 bars. Then, it wasfiltered, the filtrate evaporated and the residue crystallized in ethylacetate. 52 g of the expected product were thus obtained.

Yield: 77%

NMR spectrum (CDCl₃) δppm=6.38, d, (J=7 Hz), amidic protons (--CO--NH--)(exchangeable) Centred on 4.18, m, 1 tropanic proton at 3 3.60, m,tropanic protons at 1 and 5 2.70, s, N--H proton (exchangeable) 1.96, s,3 acetyl protons (CH₃ CO--) between 2.20 and 1.15, m, 8 tropanicprotons.

By the same process, but using ethyl chloroformiate (instead of acetylchloride), β-3-ethoxycarbonylamino nor-tropane (VIII) was obtained.

Melting point: 252° C.

Empirical formula: C₁₀ H₁₉ ClN₂ O₂

Molecular weight: 234.72

Elementary analysis:

    ______________________________________                                                   C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             51.17       8.16   11.94                                         Obtained (%) 50.98       8.05   11.98                                         ______________________________________                                    

NMR spectrum (CDCl₃): δppm=5.55, d, --NH--COO-- 4.08, q, and 1.18, t,(J=7 Hz): --COOCH₂ --CH₃ 1.96, s,: NH-- 3.51, m, tropanic protons at 1and 5 3.91, m, 1 tropanic proton at 3 centred on 1.72, m, tropanicprotons at 2, 4, 6 and 7.

2nd stage β-3-amino N-p-fluorobenzyl nor-tropane (III)

Code number: 103

A solution of 17 g of β-3-acetamido nor-tropane [(VIII) obtained in thepreceding stage], of 21 g of p-fluorobenzyl chloride and of 18 ml oftriethylamine in 250 ml of acetone was heated to reflux for 12 hours.Then it was filtered, the filtrate was evaporated, and the residue wasdissolved in 200 ml of methylene chloride, washed with water, dried onsodium sulfate and the solvent was evaporated. 21 g of raw product wereobtained which was dissolved in 250 ml of sulphuric acid at 10% and thesolution was heated to reflux for 24 hours. It was washed with 100 ml ofmethylene chloride, the aqueous solution was alkalized with concentratedpotash, extracted with methylene chloride, dried on sodium sulfate andthe solvent was evaporated. 17 g of raw product were obtained, yield96%, which was used directly in the synthesis of the correspondingcompound of formula (I) with code No. 19 and described in example 1.

NMR spectrum (CDCl₃): δppm=centred on 7.08, m, and 3.52, s, 6H(benzylic)centred on 3.15, m, tropanic protons at 1 and 5 centred on 2.94, m, 1tropanic proton at 3 between 2.20 and 1.15, m, 8 tropanic protons 1.11,s, NH₂ (exchangeable).

By the same process, but from β-3-ethoxycarbonylamino nor-tropane (VII)described in the preceding stage, the β-3-amino N-parafluorobenzylnor-tropane (III) of code number 103 was also obtained.

By the same process, but from the corresponding reagents, the β-3-aminoN-nor-tropanes of formula (III) were obtained. Apart from the fewcompounds of formula (III) given in table III, the majority of thecompounds (III) were used raw (after checking by thin layerchromatography) in the synthesis of the corresponding compounds offormula (I).

                                      TABLE III                                   __________________________________________________________________________     ##STR73##                                                                                                   Melt-                                                                     Molec-                                                                            ing                                            Code               Empirical                                                                             ular                                                                              point                                                                              Yield                                                                             Elementary analysis - NMR                                                     spectrum-                             No. R         Form formula weight                                                                            (°C.)                                                                       (%) IR spectrum                           __________________________________________________________________________                                            Elementary analysis:                                                                    C   H   N                    98                                                                                ##STR74##                                                                              dimaleate                                                                          C.sub.22 H.sub.28 N.sub.2 O.sub.8 + 4.5 H.sub.2                                       462.87                                                                            150  59    Cal. Obt.                                                                         (%) (%)                                                                           57.08 57.14                                                                       6.45 6.19                                                                         6.05 5.92              99                                                                              ##STR75##                                                                              base C.sub.14 H.sub.19 BrN.sub.2                                                           295.22                                                                            oil  63                                                                                 ##STR76##                              100                                                                              ##STR77##                                                                              "    C.sub.15 H.sub.19 F.sub.3 N.sub.2                                                     284.32                                                                            oil  71                                                                                 ##STR78##                              101                                                                              ##STR79##                                                                              "    C.sub.14 H.sub.19 BrN.sub.2                                                           295.22                                                                            oil  52                                                                                 ##STR80##                              102                                                                              ##STR81##                                                                              "    C.sub.14 H.sub.19 FN.sub.2                                                            234.31                                                                            oil  66                                                                                 ##STR82##                              103                                                                              ##STR83##                                                                              "    C.sub.14 H.sub.19 FN.sub.2                                                            234.31                                                                            oil  96                                                                                 ##STR84##                            __________________________________________________________________________

The derivatives of formula (I) were tested on laboratory animals andshowed neuroleptic properties.

These properties were demonstrated on mice particularly by the test ofantagonism to apomorphine straightening, carried out in accordance withthe method described by G. Gouret et alia in J. Pharmacol. (Paris) 1973,4, 341.

The effective dose 50 (ED 50) obtained by intraperitonealadministration, in accordance with the above-mentioned test, of thederivatives of formula (I) and SULPIRIDE chosen as reference compound,are given in table IV below.

Acute toxicity was studied on mice by intraperitoneal administration,and the estimated lethal doses in accordance with the method describedby MILLER and THINTER Proc. Soc. Exper. Biol. Med. 1944, 57, 261, arealso shown in table IV.

                  TABLE IV                                                        ______________________________________                                        Tested    Acute toxicity (mice                                                                        Apomorphine straightening                             compound  LD 50 mg/kg/i.p.)                                                                           ED 50 (mg/kg/i.p.)                                    SULPIRIDE 170           37                                                    ______________________________________                                         3        300           0.04                                                   8        220           0.035                                                  9        240           0.01                                                  10        325           0.035                                                 16        240           0.01                                                  19         90           0.010                                                 20        >400          0.034                                                 21         85           0.07                                                  22        140           0.021                                                 23        >400          0.07                                                  24        160           0.05                                                  25        100           0.03                                                  26        140           0.011                                                 27        >400          0.034                                                 28        >400          0.12                                                  29        180           0.012                                                 30        230           0.3                                                   32        140           0.05                                                  33        >400          0.19                                                  35         80           0.07                                                  37        170           0.16                                                  40        130           0.05                                                  41        225           0.03                                                  42         61           0.05                                                  43        120           0.03                                                  48        310           0.21                                                  49        120           0.08                                                  51        140           0.03                                                  60         75           0.027                                                 61         80           0.02                                                  62         60           0.04                                                  64         83           0.008                                                 67        100           0.038                                                 68         47           0.02                                                  71        120           0.11                                                  72        110           0.04                                                  73        170           0.02                                                  74        250           0.035                                                 75        >400          0.021                                                 83        140           0.031                                                 ______________________________________                                    

As the results given in this table show, the differences betweeneffective doses and lethal doses 50 is sufficient to allow thederivatives of formula (I) to be used in therapeutics.

These latter are particularly prescribed in the treatment ofdisturbances of the psychism.

They will be administered orally in the form of tablets, pills orcapsules containing 50 to 300 mg of active ingredient (3 to 8 per day),in solution form containing 0.1 to 1% of active ingredient (10 to 40drops once to thrice per day), by parenteral administration in the formof injectable ampoules containing 5 to 100 mg of active ingredient (3 to8 ampoules per day).

We claim:
 1. A compound having the formula ##STR85## wherein ACO isselected from the group consisting of ##STR86## or a pharmacologicallyacceptable acid addition salt thereof.
 2. A compound as claimed in claim1 in which ACO is ##STR87##
 3. A compound as claimed in claim 1 in whichACO is ##STR88##
 4. A compound as claimed in claim 1 in which ACO is##STR89##
 5. A compound as claimed in claim 1 in which ACO is ##STR90##6. A compound as claimed in claim 1 in which ACO is ##STR91##
 7. Acompound as claimed in claim 1 in which ACO is ##STR92##
 8. A compoundas claimed in claim 1 in which ACO is ##STR93##
 9. A compound as claimedin claim 1 in which ACO is ##STR94##
 10. A compound as claimed in claim1 in which ACO is ##STR95##